A major problem in the treatment of cancer is the emergence of tumor cell resistance to chemotherapeutic agents and the subsequent patient relapse. These cancer victims may fail to respond to any antitumor agent since these tumor cells tend to exhibit clinical resistance to many drugs. This phenomenon is termed multidrug resistance (MDR). MDR is associated with certain alterations in tumor cells, including an over-expression of a certain high molecular weight membrane glycoprotein and a decrease in the ability of the tumor cell to accumulate and retain chemotherapeutic agents.
Drugs of proven antitumor chemotherapeutic value to which multidrug-resistance has been observed include vinblastine, vincristine, etoposide, teniposide, doxorubicin (adriamycin), daunorubicin, plicamycin (mithramycin) and actinomycin D. Many tumors are intrinsically multidrug-resistant (eg. adenocarcinomas of the colon and kidney) while other tumors acquire multidrug-resistance during therapy (eg. neuroblastomas and childhood leukemias).
Agents are available which can restore drug sensitivity to some multidrug resistant tumor cells. Among these agents known to possess this property are calcium transport blockers (e.g. verapamil) and calmodulin inhibitors (e.g. trifluoperazine). Clinical use of these compounds has been limited by their extremely toxic side effects (Twentyman, P.R. et al., Int. J. Radiat. Oncol. Biol. Phys., 12, 1355 (1986)).
The present invention describes a use for various cyproheptadine derivatives that are effective in increasing the sensitivity of tumor cells resistant to anticancer chemotherapeutic agents, such as vinblastine. These compounds have the effect, as described herein, of reducing the resistance of multidrug resistant tumor cells and potentiating the sensitivity of cells susceptible to antitumor agents.
Given their efficiency in reversing multidrug resistance, these compounds are expected to have broad clinical application and may play a significant role in fighting cancer.
An object of the present invention is to provide a method for increasing the sensitivity of tumor cells which are susceptible to certain antitumor agents using (-)-1-cyclopropylmethyl4-(3-trifluoro-methylthio-5H-dibenzo[a,d]cyclohepte n-5-ylidene)-piperidine, (+)-1-cyclopropylmethyl-4-(3-iodo-5H-dibenzo[a,d]cyclohepten-5-ylidene)pip eridine, 4-amino-5-chloro-2-methoxy-N-((5-(l-methyl-4-piperidinylidene)-5H-dibenzo[ a,d]cyclohepten-3-yl)methyl)-benzamide, 3,4,5-trimethoxy-N-((5-(l-methyl-4-piperdinylidene)-5H-dibenzo[a,d]cyclohe pten-3-yl)methyl)benzamide and diethyl 1,4-dihydro-2,6-dimethyl-4-(5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d ]cyclohepten-3-yl)-pyridinedicarboxylate or a pharmaceutically acceptable salt thereof.
An additional object of the present invention is to provide a method for treating multidrug resistant or drug sensitive tumor cells which preferably involves administering to a patient in need of such treatment a therapeutically effective dosage of a compound of this invention in combination with, prior to or concurrent to the administration of a therapeutically effective dosage of an antitumor chemotherapeutic agent.
A further object of this invention relates to a method of preventing the emergence of multidrug resistant tumor cells during a course of treatment with antitumor chemotherapeutic agents. to provide a method of reducing the effective dosage of an antitumor chemotherapeutic agent during a course of treatment.
The present invention has met the above described need by providing a method which preferably involves administering to a person a therapeutically effective dosage of a compound of this invention in combination with or concurrent to the administration of a therapeutically effective dosage of an antitumor chemotherapeutic agent for the direct treatment of multidrug resistant tumors. In addition, the compounds of the present invention may have a lower propensity to induce extrapyramidal side effects that are experienced with many tricyclic compounds.